Beatrice, the windowed mother of the four Reed sisters must consider selling the family home, a something she's totally unprepared for. Her daughters. Alex, Georgie, Teddy and Frankie are brought together by the sale of their family home and the passing of their father. Georgie, herself, must deal with her unemployed husband who spends all his time in his bathrobe, perfecting his lounge act. Teddy, who hasn’t been around for sometime, is back to reclaim Mitch, her ex-husband and father to her daughter. She's surprised to find out that her baby sister, Frankie, now has him. The four women put their own problems aside, however, when their mother, is involved in a car accident. Together they join forces to help their mother accept the loss of her husband and deal with her alcoholism.

While planning her fifteenth anniversary party, Alex secretly hires a private investigator to see if her husband is having an affair. Teddy and her teenage daughter, Cat, have moved in with Georgie and her family. Fearing what she may find, Alex asks Georgie to go with her to a hotel room where the private detective last saw Wade. Georgie and Alex find Wade, alone and dressed in women's lingerie. Alex spends the night with her slightly alcoholic mother, then decides to go through with the party and leave Wade afterwards. But Wade tells Alex he still loves her and asks her to reconsider.

Leaning heavily on Frankie's guilty conscience, Georgie convinces her to hire Teddy at her office. Teddy reluctantly accepts an entry-level position, but soon finds it intolerable to have her younger sister boss her around as well as date her ex-husband. When the office has a computer malfunction, Teddy gets blamed and fired. Once the source of the problem is discovered, Frankie realizes she has accused the wrong person. Ashamed for being so judgmental, she offers to hire Teddy back. Teddy has already found a new job, but she accepts Frankie's apology and, in a burst of sisterly goodwill, offers to help her restore the computer data.

On the one-year anniversary of their father's death, the Reed sisters gather at his gravesite to honor his memory. They arrive in time to see a mysterious woman place red roses on their father's grave. The woman turns out to be Dr. Reed's nurse of many years, Belle Aderlee. When Frankie presses for further details, the nurse suggests she ask her mother for the story. Over the protests of her sisters, Frankie confronts her mother. She answers the question by reading a letter their father left behind. Meanwhile, Georgie considers romance with an old flame, who returns to town for his mother’s funeral. Later, as the girls sort through their mixed feelings, they decide to remember their father as a loving parent, who happened to be very human as well.

Georgie has always been quiet and timid, but since her husband, John, has been out of work, she's forced herself to speak up more at the office. Consequently, she now faces the awesome task of having her boss come to the house for dinner. Alex is in shambles over her plastic surgeon husband, Wade and his money mishaps. After a fight with Frankie, Mitch calls a party line and unknowingly gets Teddy.
Later, Frankie has some news to share about her and Teddy's ex-husband, Mitch. Teddy is shocked by the revelation. In the midst of this, Georgie carves the stuffed goose and finds her son's missing pet cooked inside. Later, as they all share a pizza, Georgie is given a promotion by her boss. His logical is that anyone able to handle such an evening would have no trouble managing a busy, high-pressure office.

Frankie is finally marrying Mitch. Alex has decorated her house for the big event, but there is still controversy whether or not Teddy will come. Just as expected, Teddy comes through with a less then enthused attitude about the event. Teddy reveals to Mitch who he was actually talking to on the phone. Deciding it’s a sign, Frankie informs Mitch that she can't go ahead with the wedding.
Meanwhile, Alex is paid a visit from Wade’s business partners. They know Wade has left and want Alex to reimburse them for their loses.

Georgie is not prepared for the situation fate suddenly bestows upon her. Her youngest son, Evan, is diagnosed with leukemia. Georgie and husband, John, begin a constant vigil at the hospital. Evan has a good chance of recovery, but there is a long battle ahead for him. Alex, Teddy and Frankie worry in private, because Georgie hasn't given in to her feelings, instead, remaining stoic and in control. Meanwhile, Teddy makes plans to leave town.

After being diagnosed with Leukemia, Evan starts chemotherapy treatments. This serves to prompt John into sanity. Georgie wants Evan to have a quiet tenth birthday, but Alex disagrees and plans an extravagant party for him. Teddy tries to reconnect with Cat, who is staying with her father, Mitch. But Teddy has started drinking again, and Georgie forces her to move out of their house. When a client wants Frankie to fly to Tokyo on the day of Evan's party, she feels guilty. Bea talks Teddy into going to Alcoholics Anonymous with her. And Evan thinks he's going to die because everybody is making his party into such a big event. Georgie explains that it's just to make his birthday extra special because he isn't feeling well. And Frankie makes it to Evan party before her flight.

John continues to receive orders for his vocal tape while he tries to help Mitch with his finances. Mitch needs $25,000 to keep his fish market open. Georgie suggests that he borrow the money from Frankie, but Mitch disagrees. Teddy meets Hank Seawell, a prestigious photographer whose pictures of the homeless she once tried to paint. Seawell has been hired by Alex to take photos of her and Wade. At Teddy's suggestion, Alex decides to spend more quality time with Wade and gets tickets to an interactive theatre show. One of the stars of the show, Tiffany Blue, happens to be having an affair with Wade. Finally, Mitch reluctantly forms a financial partnership with Frankie to save his fish market. When they go to City Hall to file the partnership papers, they decide to get married instead.

Alex and Wade meet with their lawyers to negotiate their divorce settlement. Meanwhile, Frankie savors her secret marriage to Mitch. Alex tells her sisters that Wade is trying to kill her, but no one believes the overemotional Alex. Wade discovers that his girlfriend, Tiffany Blue, has hired a hit man to kill the troublesome Alex. Wade thwarts the attempt on Alex's life and decides Alex can have everything she wants in the divorce settlement. Frankie finally tells Teddy about the marriage. Teddy, who has just discovered she is pregnant by Mitch, remains silent. Georgie seeks the advice of her sisters about bowling in a tournament. She feels it may be wrong to have fun while her son is so seriously ill. Georgie decides to bowl in the tournament and enjoys helping her team win.

While Alex is depressed about her failed marriage, Frankie and Mitch prepare to make their secret marriage public. When Cat learns the news of Frankie and Mitch‘s marriage, she runs away, bringing Teddy and Mitch together and making Frankie feel left out. Although Teddy is pregnant by Mitch, she cannot make herself tell him.
Meanwhile, Alex decides she wants to be more free-spirited like her sister Teddy. She starts dressing like Teddy - with a leather jacket and a pair of blue jeans - a far cry from Alex’s usual silk or designer wears. At the height of her breach of insanity, Alex even jumps in a fountain like her sister once did. Teddy, feeling less than free at the moment, goes to get an abortion but ends up having a change or heart - even if it means a change of lifestyle.

Alex worries about attending her high school reunion due to her pending divorce. However, at the reunion, she sees fellow classmate, David, who cares little about her success and genuinely likes her. Meanwhile, Frankie, now married to Mitch, finds a condom inside one of Cat's books, “Little Women“. Mitch, Frankie and Teddy are worried until they learn that the condoms were given out in Cat's health class. Alex spends a romantic weekend with David who teaches her to stop caring so much about what other people think.
Bea begins dating Judge Truman Ventner, who previously revoked her newly restored driver's license. Eventually, Bea lets Truman kiss her and finds she enjoys it. After a lull in the romance department, Georgie and John rekindle their sexual attraction. But when Frankie discovers what has happened in David’s past might just change the future for him and Alex.

Hank Seawell and Teddy prepare for the opening of Hank's photography exhibit, a major event, hosted by the Hospital Women's League and Alex, the new Chairperson. Wade brings his young girlfriend to the event. Prompting Alex to bring a handsome but inarticulate man, Victor, who just so happens to be working on her toilet at the time. While trying to make Wade jealous she may have started another fire.
When the photos of Teddy (naked) are unveiled, an irate councilman closes the exhibit. John is insulted while a guest on a popular radio show, his children's favorite.

When Georgie misses Trevor's soccer game because she has to take Evan to the doctor, Trevor breaks the windows of a vacant house. When Teddy tells her friend, Hank, that she is pregnant, he asks her to move to New York with him. Teddy finally tells the rest of her family about her pregnancy, omitting who's baby it is. While not entirely shocked by Teddy’s news, given her history, are not happy either. And although Mitch wants to claim the child as his, he's uncertain what to tell Frankie, his wife. Meanwhile, Alex decides to pursue a career in interior design, starting with her mother's apartment. While redecorating, Georgie and Alex accidentally walk in on Bea and Truman in a compromising position.

Alex's sisters talk her into joining a computer dating service. Victor, a plumber's apprentice, overhears and asks her out. Alex refuses and goes out with a computer match, which turns out to be a disaster. Alex goes out with Victor, gets drunk and wakes up in bed with him the next morning. John and Georgie fight with their neighbor, Mr. Rattner, about their tree that drops leaves in his yard. Evan, whose leukemia prevents him from playing with friends, is up in the tree when Mr. Rattner cuts it down. Frankie has to make a big effort to get along with her abrasive mother-in-law, Naomi Margolis. Finally, Alex surprises Victor by showing up at the pool hall for a date with him.

Alex wants Bea to have the perfect wedding, but Bea doesn't like her daughter's plans. While Alex spends a romantic evening with her ex-husband, Wade, Reed informs them that she wants to quit college to be with Kirby. Later Reed informs everyone that she has married Kirby, and Alex reacts by breaking every piece of crystal in her house. Frankie is concerned that Georgie, who is seven months pregnant, may be over-exerting herself, so she hires a housekeeper for Georgie. And Georgie ends up feeling stressed and “hormonal” as a result. Bea and Truman decide they want to elope. And with the whole place prepared for a wedding service, Reed and Kirby get Alex's blessing and agree to go through with the ceremony.

Mitch's clam chowder wins a contest, and Mitch becomes "Chowder King of Chicago." A female reporter flirts with Mitch and writes a flattering article about his store, filling it with customers. Teddy meets an eccentric and attractive millionaire, Simon Bolt, who asks her out. Teddy refuses, but Simon is persistent, eventually convincing Teddy to let him invest in her company, “Teddywear.”

Teddy saves negative reviews of her work by fashion columnist Diana Gottfried and holds a press conference in retaliation. Later, Teddy confronts Diana at a restaurant. When Diana is rude to her, Teddy hits her in the face with a pie. Teddy feels victorious, until Diana sues her for battery and $3,000. While backing out of the driveway in her new car, Georgie has an accident involving the neighbor's dog, Speedy. When Alex goes to the cash machine to withdraw money, it accidentally gives her an additional $2,000, which the bank refuses to take back. She decides to spend the money on a cocktail jacket she saw in a store window earlier that day. In preparation for shopping Alex picks up the shopping bag containing Speedy, thinking it is a purse her sister wants to return to the store. Alex and the salesgirl are shocked by what they find inside.

Alex, Georgie, Frankie and Teddy meet in their favorite booth at the Sweet Sixteen, a 1950s cafe, to celebrate its thirty-fifth anniversary. The next day at a church seminar, Alex gives an inspirational talk to other cancer survivors like herself. After the program, Norma Lear, producer of Harry Busby's local TV talk show, asks Alex to appear as a guest on the show. After Harry chokes and dies while laughing at one of Alex's jokes, and Norma talks Alex into replacing Harry. Wanting to be close to Cat while she recovers from her rape, Teddy stays at Mitch's house. Soon, Teddy and Mitch mull reconciliation. Georgie is upset when the Sweet Sixteen burns down. Frankie and Georgie try to convince the owners of the "Sweet Sixteen" ice cream shop to rebuild. Frankie comforts Georgie with news that she bought what's left of the Sweet Sixteen and wants Georgie to be her business partner.

When Kyle Parks, Cat’s attacker, makes bail Teddy begs Detective Falconer (George Clooney) to help them. Alex lets John make a musical appearance on the show, after which Alex's producer, Norma, asks John to sing on a regular basis. Frankie enjoys running her new purchase, the old Sweet Sixteen Cafe. She is also very excited about the new man she is corresponding with over her computer. Cat demands that Teddy let her continue to be free, but has a later run in with Kyle.

Kyle Parks is brought to trial. Teddy is afraid that Kyle's defense attorney, Barbara Buckley, will try to Kyle off for Cat‘s rape. But Teddy notices a quiet young woman, Mary McConnell, who attends the trial every day and learns that Mary was also raped by Kyle. Unfortunately, the judge refuses to allow Mary's testimony during Cat's trial. After listening to many days of testimony about rape, Georgie has some disturbing reminiscences. She confesses to her sisters that when she was 18, a young boyfriend raped her. She suppressed the bad memory for all these years.

Frankie owning the Sweet Sixteen Café, takes a chance and hires her nephew Trevor as cashier. Frankie sees Trevor take money and later confronts Trevor, who denies stealing the money. While helping Truman plan a surprise birthday party for Bea; Alex notices that his behavior is strange. When Truman becomes disoriented on various occasions, Alex takes Truman to a doctor who explains that Truman has Alzheimer's. Truman begs Alex not to tell Bea.
And Simon Bolt comes back from the dead! Presumed dead, Simon confesses that he staged his death to escape the pressures of the business world. He claims he's on his way to Tahiti, where he intends to live. Teddy lets Simon stay with her for a few days, but it soon becomes apparent he has no intention of leaving. Falconer tells Teddy he doesn't want to see her until she resolves her relationship with Simon.

Alex has a conjugal visit with Big Al, who is in a country-club-type prison. Big Al plans to sell his beloved Pricetown to his arch rival, "Aaron the Bargain Baron" so he can pay his debt to the IRS. When Alex learns of this, she challenges Aaron to a poker game -- winner take all. Despite the fact that Alex doesn't know how to play poker! Meanwhile, Georgie is back in the real estate business to help pay the costs of going to therapist Dr. David Caspian. In her therapy, Georgie begins to believe that she was molested by her father. She tells her husband, John and then reluctantly tells Bea and her sisters. None of them believe Georgie. Teddy has recurring nightmares that Falconer died in a plane crash. The newlyweds find a house in the suburbs. Their happiness abruptly ends when Falconer, who is testifying against a gangster, is blown up in his car while Teddy watches helplessly.

Alex goes on trial to fight the murder charge. She learns that the judge trying the case is biased -- and not in her favor. Meanwhile, Teddy meets Daniel Albright's wife, Cynthia, and confides in her the real reason that she's staying close to Albright. Teddy also learns that Daniel is beating Cynthia, who finally leaves him and without revealing Teddy's confidence to her husband. Teddy's daughter, Cat, is tired of having a married boyfriend and ends the relationship after seeing him with his wife and two children.

After his wife leaves him, Daniel Albright asks Teddy to move in with him and proposes marriage. Teddy thinks that this will give her a good opportunity to obtain evidence on Albright's illegal activities. Unfortunately, Albright's henchman, Martin, discovers that Lucky is still alive, meaning Teddy staged her shooting of him. However, before Martin can do any real harm, Lucky and Teddy let the police know about a heroin stash in Albright's airplane. Albright is arrested.
Meanwhile, after dealing with an annoying hypochondriac patient, Charley decides to return to her work at the clinic instead of remaining at the posh medical firm. By reluctantly hosting a pledge drive for public television, Alex helps Norma get a permanent position at the TV station as executive producer of 'Alex Reborn,' with Alex as the star.

Reed returns unexpectedly to Winnetka, and tells Alex that her husband, Kirby, took her baby and left her. Later, Alex learns the truth and ends all communication with Reed. Alex, Teddy, Charley and Bea plan a party for Georgie's 40th birthday. However, they plan to re-celebrate her 10th birthday, since Georgie is depressed about her advancing age. Georgie has a fantasy that she is being interviewed by Willard Scott on her 100th birthday, but has no accomplishments in her life to show for it. Teddy proudly buys Cat a new car as her college graduation gift. After they get carjacked, Teddy buys handguns for her and Cat. When Teddy sees the carjacker again, she confronts him, and he shoots her. When Teddy does not arrive for Georgie's party, everyone wonders where she is.

Shot in the head by a carjacker she confronted, Teddy appears at first to be only minimally injured. But she soon lapses into a coma, to the distress of her family. While Teddy's loved ones hold vigil, her unconscious mind wanders to the memory of a family camping trip she took as a child. The girls get lost in the woods and must struggle to get back to their family. In real life, Alex hears about Dr. Gabriel Sorenson, a brilliant doctor who specializes in head wounds like Teddy's, and contacts him, convincing him to take Teddy's case.